Neural progenitor cells persist throughout the adult forebrain ventricular zone (VZ), and have been found in species ranging from canaries to humans (Alvarez-Buylla et al., “Neuronal Stem Cells in the Brain of Adult Vertebrates,” Stem Cells 13:263-72, (1995); Goldman, S. et al., “Neuronal Precursor Cells of the Adult Rat Ventricular Zone Persist into Senescence, with No Change in Spatial Extent or BDNF Response,” J. Neurobiology 32:554-566 (1997); Goldman, S. et al., “Neural Precursors and Neuronal Production in the Adult Mammalian Forebrain,” Ann. N.Y. Acad. Sci. 835:30-55 (1997); Goldman, S. A. et al., “Strategies Utilized by Migrating Neurons of the Postnatal Vertebrate Forebrain,” Trends in Neurosciences 21:107-114 (1998)). To the extent that neurogenesis and oligoneogenesis by these endogenous progenitors may be induced or supported exogenously, these cells may provide a cellular substrate for repair in the adult central nervous system (CNS). In culture, adult-derived progenitors have been found to respond to mitogens, in particular epidermal growth factor (EGF) and fibroblast growth factor 2 (FGF2), with increased division and neuronal mitogenesis (Palmer, T. D. et al, “FGF-2-Responsive Neuronal Progenitors Reside in Proliferative and Quiescent Regions of the Adult Rodent Brain,” Mol. Cell Neurosci. 6:474-86 (1995); Reynolds, B. A. et al, “Generation of Neurons and Astrocytes from Isolated Cells of the Adult Mammalian Central Nervous System,” Science 255:1707-10 (1992); Richards, L. J. et al, “De Novo Generation of Neuronal Cells from the Adult Mouse Brain,” Proc. Nat'l. Acad. Sci. USA 89:8591-5 (1992); Vescovi, A. L. et al, “bFGF Regulates the Proliferative Fate of Unipotent (neuronal) and Bipotent (neuronal/astroglial) EGF-generated CNS Progenitor Cells,” Neuron 11:951-66, (1993)). Furthermore, neurons generated from them respond to brain-derived neurotrophic factor (BDNF) with enhanced migration, maturation, and survival in vitro (Goldman, S. et al., “Neuronal Precursor Cells of the Adult Rat Ventricular Zone Persist into Senescence, with No Change in Spatial Extent or BDNF Response,” J. Neurobiology 32:554-566 (1997); Goldman, S. et al., “Neural Precursors and Neuronal Production in the Adult Mammalian Forebrain,” Ann. N.Y. Acad. Sci. 835:30-55 (1997); Kirschenbaum, B. et al, “Brain-derived Neurotrophic Factor Promotes the Survival of Neurons Arising from the Adult Rat Forebrain Subependymal Zone,” Proc. Nat'l. Acad. Sci. USA 92:210-4 (1995)). Similarly, infusions of EGF and FGF2 into the adult ventricular system stimulate mitotic gliogenesis and neurogenesis, respectively (Craig, C. G. et al., “In Vivo Growth Factor Expansion of Endogenous Subependymal Neural Precursor Cell Populations in the Adult Mouse Brain,” J. Neuroscience 16:2649-58 (1996); Kuhn, H. G. et al, “Epidermal Growth Factor and Fibroblast Growth Factor-2 Have Different Effects on Neural Progenitors in the Adult Rat Brain,” J. Neuroscience 17:5820-5829 (1997)), while intraventricular infusions of BDNF can enhance neuronal migration to the olfactory bulb, rostral migratory stream, and adjacent forebrain (Pencea, V. et al, “Infusion of BDNF into the Lateral Ventricle of the Adult Rat Leads to an Increase in the Number of Newly Generated Cells in the Fore-, Mid- and Hindbrain Parenchyma,” Soc. Neurosci. Abstr. 25:2045 (1999); Zigova, T. et al, “Intraventricular Administration of BDNF Increases the Number of Newly Generated Neurons in the Adult Olfactory Bulb,” Molec. Cellular Neurosci. 11:234-245 (1998)). Although intriguing, these studies have been limited by the need for chronic intraventricular catheterization, with its dependence upon protein availability and stability, the uncertain tissue bioavailability of intraventricularly administered proteins, and the risks of infection and catheter loss inherent in chronic ventriculostomy.
The striatum is the major target of the progressive neurodegeneration that occurs in Huntington's Disease, in which the major neuron loss is that of the striatal GABA-producing neurons. Other degenerative diseases, such as amyotrophic lateral sclerosis (ALS; also known as Lou Gehrig's Disease), and progressive muscular atrophy, result at least in part from a decay of motor neurons which are located in the ventral horn of the spinal cord.
While there are some therapies available to treat the symptoms and decrease the severity of such diseases (e.g., L-dopa to treat Parkinson's Disease), there currently exists no effective treatment to prevent or reduce the degeneration of most of the above-mentioned classes of affected neurons, or to promote their repair. Several naturally-occurring proteins have been identified based on their trophic activity on various neurons. These molecules are termed “neurotrophic factors”. Neurotrophic factors are endogenous, soluble proteins that can stimulate or regulate the production, survival, growth, and/or morphological plasticity of neurons. (See Fallon and Laughlin, Neurotrophic Factors, Academic Press, San Diego, Calif. (1993)).
The known neurotrophic factors belong to several different protein superfamilies of polypeptide growth factors based on their amino acid sequence homology and/or their three-dimensional structure (MacDonald et al., “A Structural Superfamily Of Growth Factors Containing A Cystine Knot Motif,” Cell 73:421-424 (1993)). One family of neurotrophic factors is the neurotrophin family. This family currently consists of nerve growth factor (NGF), brain derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), neurotrophin-4 (NT-4), and neurotrophin-6 (NT-6).
On the basis of current studies, and of their limitations in practice, it will be appreciated that a need exists for an efficient means of delivering neurotrophic differentiation agents to the adult ventricular zone, the site of residual progenitor cells in the adult brain. Furthermore, in view of the fact that many nervous system disorders and diseases have no known cure, there is a need in the art for new methods of inducing neuronal production in the adult brain, especially for treating Huntington's Disease and other degenerative neurological conditions, as well as stroke and traumatic brain injury.
The present invention is directed to overcoming these and other deficiencies in the art.